Research

Seed Grant Profile

49

Evaluation and Modeling of Redox Regulation of NF-kappaB in Acute Lymphoblastic Leukemia cells: Role in Drug Resistance

There has been increasing interest in the relationship between the NF-kB anti-apoptosis
signaling pathway and the generation of reactive oxygen species (ROS) in pediatric
acute lymphoblastic leukemia (ALL) post-therapy. Our previous results suggest
that ALL cells with high levels of constitutively activated NF-kB have increased
resistance to ROS-generating chemotherapeutic agents like doxorubicin. In particular,
we have studied two patient-derived ALL cells lines which show differential
regulation of NF-kB-activation levels post-treatment with doxorubicin: EU-1
(drug-resistant line) shows high levels of activated NF-kB post-therapy in contrast to EU-3
(drug-sensitive).

We hypothesize that key redox buffering components protect ALL cells from
ROS-generating agents by preventing ROS-mediated downregulation of NF-kB. This
hypothesis is supported by studies showing increased intracellular glutathione
is associated with poor prognosis in pediatric lymphoblastic leukemias. We
will evaluate the effect of redox-buffering components on the level of ROS
induced by doxorubicin in the two patient-derived cell lines (EU-1 and EU-3).
We then will use differences between the cell lines to generate redox-balance
computational models of dox-sensitive and dox-insensitive cells. This will
permit cell-line specific simulation of redox-conditions and identification
of variations in key redox enzyme levels involved in regulating NF-kB activation
in the two model cell lines. These results may have clinical significance in
elucidating the role of redox-regulatory components in creating resistance
to important ROS-generating chemotherapeutic agents used to treat acute lymphoblastic
leukemia.